The compound (±)-2-[phenyl(1-methyl-1H-pyrazol-5-yl)methoxy]-N,N-dimethylethanamine, also referred to as (±)-5-[α-(2-dimethylaminoethoxy)benzyl]-1-methyl-1H-pyrazole, or Cizolirtine, of formula (I)
is described in the European Patent EP 289 380. This compound is a potent analgesic which is currently in phase II clinical trials.
The two enantiomers of Cizolirtine, hereinafter referred to as (+)-I and (−)-I, have been previously obtained by optical resolution of the Cizolirtine racemate by fractional crystallization with optically active acids (as described in International Patent Publication WO 99/02500) such as, for instance, with (−)- and (+)-di-p-toluoyltartaric acid (Torrens, A.; Castrillo, J. A.; Frigola, J.; Salgado, L.; Redondo, J. Chirality, 1999, 11, 63). The study of their analgesic activities has shown that the dextrorotatory enantiomer, (+)-I, is more potent than the (−)-I. An enantiomerically pure compound synthesis (EPC synthesis) starting from ethyl (R)-mandelate of the intermediate permitted the assignment of the (R) absolute configuration to the (+)-I isomer (Hueso-Rodriguez, J. A.; Berrocal, J.; Gutiérrez, B.; Farré, A.; Frigola, J. Bioorg. Med. Chem. Lett. 1993, 3, 269).
The (±)-Cizolirtine has been prepared by O-alkylation of compound (±)-II of formula II:

The pure enantiomers of Cizolirtine (+)-I and (−)-I may be prepared by separately O-alkylating the enantiomerically pure intermediates (+)-II and (−)-II.
The enantiomerically pure compounds (+)-II and (−)-II are obtained either by reduction of a compound of formula III, which yields (±)-II as a racemate, followed by procedures of optical resolution of the racemate (±)-II, such as by fractional recrystallization from solvents or column chromatography [J. A: Hueso, J. Berrocal, B. Gutiérrez, A. J. Farré y J. Frigola, Bioorg. Med. Chem. Lett. 1993, 3, 269], or by EPC synthesis starting from the prochiral ketone of formula III:

The enantioselective reduction of prochiral ketones in organic synthesis to obtain secondary alcohols with high enantiomeric purity is of high interest since they can be valuable intermediates for the manufacture of active compounds. Accordingly, a number of strategies for the asymmetric reduction of prochiral ketones to single enantiomer alcohols have been developed [R. Noyori, T. Ohkuma, Angew. Chem. Int. Ed., 2001, 40, 40–73, Wiley-VCH Verlag]. Particularly, the use of oxazoborolidines as ligands or catalysts constitutes a major advance in the asymmetric reduction of prochiral ketones. The use of such chiral ligands or catalysts in combination with achiral reducing agents for the preparation of (+)-I and (−)-I has been described in European Patent EP 1 029 852 B1. However, for diaryl methanols, the reduction of the corresponding ketone precursors is problematic. The chiral catalyst has to differentiate between the two aromatic rings. This can usually only be done with high selectivity if the two rings are different in terms of steric and/or electronic properties, which is not obvious in the case of Cizolirtine.
Another strategy for the enantioselective reduction of prochiral ketones with high enantiomeric excess involves the use of a diphosphane/Ru/chiral diamine/inorganic base catalyst system. However, this process leads to the formation of heavy metal complexes of Ru or elemental Ru and trace amounts of such metal are very hard to remove.
A phenyl transfer reaction to aryl aldehydes as an approach towards enantio-pure diarylalcohols has also been proposed, as an alternative to the enantioselective reduction of prochiral ketones [P. I. Dosa, J. C. Ruble, G. C. Fu, J. Org. Chem. 1997, 62 444; W. S. Huang, L. Pu, Tetrahedron Lett. 2000, 41, 145; M. Fontes, X. Verdaguer, L. Solá, M. A. Pericás, A. Riera, J. Org. Chem. 2004, 69, 2532]. For this transformation, the group of Bolm et al. developed a protocol which utilized a ferrocene-based ligand (or catalyst) and diphenylzinc in combination with diethylzinc as an aryl source [C. Bolm, N. Hermanns, M. Kesselgruber, J. P. Hildebrand, J. Organomet. Chem. 2001, 624, 157; C. Bolm, N. Hermanns, A. Classen, K. Muñiz, Bioorg. Med. Chem. Lett. 2002, 12, 1795]. Enantiomerically enriched diarylmethanols with excellent enantiomeric excess (up to 99% ee) were thus obtained in a straightforward manner. Subsequently, the applicability of air-stable arylboronic acids as an aryl source was also demonstrated [C. Bolm, J. Rudolph, J. Am. Chem. Soc. 2002, 124, 14850]. However, these systems require a high catalyst loading (of commonly 10% mol.) to achieve such high enantioselectivity. With the aim of reducing this problem, recently, the use of triphenylborane has been proposed as an alternative phenyl source in a reaction where the ferrocene-based catalyst is also used (J. Rudolph, F. Schmidt, C. Bolm, Adv. Synth. Catal. 2004, 346, 867).
However, there are still some difficulties to obtain chiral alcohols with a high yield and enantioselectivity without a high amount of catalyst. For their large-scale preparation, the application of highly efficient catalytic systems and enantioselective methods employing inexpensive starting materials and simple purification steps would be most desirable.
On the other hand, there is at the present time no example of an enantioselective addition of phenyl- or arylzinc reagents to heteroaryl aldehydes which comprise one or two nitrogen atoms, such as methyl-pyrazol aldehyde. This is understandable, since substrates containing a nitrogen heteroatom can be expected to form catalytically active complexes (or product complexes), which would usually drastically diminish the selectivity by favouring competing catalytic pathways. Indeed, it is well known in zinc chemistry that various functional groups like esters or nitrites are tolerated on the aldehyde substrates. However, Lewis-basic or coordinating functional groups often lead to drastic decreases in enantioselectivity in arylzinc addition reaction, due to their ability to complex to the zinc reagent or the active catalyst. An extreme example of this behaviour would be the asymmetric autocatalysis in the addition of zinc reagents to aldehydes as examined by Soai et al. (T. Shibata, H. Morioka, T. Hayase, K. Choji, K. Soai J. Am. Chem. Soc. 1996, 471).
Thus, to attain satisfactory ee values by an enantioselective addition reaction, an appropriate coordination of the catalyst system and the aldehyde is required. The results with unusual substrates cannot be predicted, and each addition has to be investigated separately with regard to the substrate.